Roles of protein SUMOylation in AMPA receptor trafficking, synaptic dysfunction and cognitive impairment in dementia

The National Institutes of Heath in the USA define dementia as "a set of brain diseases that can deprive patients of the ability to think well enough to do normal activities, such as getting dressed or eating. They may lose their ability to solve problems or control their emotions. Their personalities may change. They may become agitated or see things that are not there."

The most common cause of dementia is Alzheimer's disease (AD), which accounts for about 65% of all dementia, has a typical onset age of 65. AD alone affects an estimated 40 million people in the world and about 0.5 million in the UK with devastating personal and social consequences, and an annual cost of more than £23 billion.

Dementia is a progressive, age-related and currently incurable disease but remarkable progress has been achieved and new discoveries are being made all of the time. Although there are still many hurdles to overcome, there is real hope that understanding the causes of dementia will lead to more targeted treatments and ways to prevent the disease in the foreseeable future.

The brain is composed of billions of nerve cells, which pass chemical signals to each other across gaps called synapses. Synapses work by specialised receptor proteins on the receiving cell detecting chemical transmitters released from the sending nerve cell. One of the most important types of neurotransmitter receptor protein is the AMPA receptor, which are responsible for nearly all of the fast communication in the brain. In the early stages of dementia this signalling between cells goes wrong and we believe that this is because AMPA receptors are not correctly positioned to receive neurotransmitter signals.

In highly active normal nerve cells some of the AMPA receptors are removed from busy synapses by a mechanism called long-term depression (LTD). This is a tightly controlled process that is balanced by the replacement of AMPA receptors at other times to make sure the synapse is receptive to new signals. In dementia the 'checks and balances' in this process stops working and too many AMPAR receptors are removed and they are not replaced. Because synapses have to be active to be maintained, this loss of AMPA receptors causes the synapse to degenerate and eventually the nerve cell to die. As more and more connections are lost and nerve cells die the brain loses the ability for work properly.

The purpose of our work is to find out what goes wrong with the processes controlling synaptic AMPA receptors in dementia. Our hypothesis is that the proper targeting and anchoring of AMPA receptors requires the involvement of a process called SUMOylation. This is when a small protein called SUMO attaches to a target protein and changes its characteristics. In the past few years it has been shown that SUMOylation plays major roles in many diseases including cancer and stroke, and it has been strongly implicated in Parkinson's disease, mental retardation and Alzheimer's disease.

We recently discovered that SUMOylation plays a key role in controlling AMPA receptors in normal nerve cells and we intend to investigate how it fails in dementia and what we can do to correct the dysfunction.

Understanding the fundamental causes of dementia is one of the most important challenges in neuroscience. Synaptic dysfunction, with a persistent and pathological enhancement of LTD, is the earliest and most reliable indicator of dementia pathogenesis. LTD is mediated by dynamic changes in synaptic AMPARs and we have shown that activity-dependent AMPAR trafficking requires protein SUMOylation. More recently we have obtained preliminary data revealing that SUMOylation is a key regulator of both NMDAR-LTD and mGluR-LTD.

The purpose of this application is to test the hypothesis that dysregulation of synaptic protein SUMOylation is a causative factor in the defective AMPAR trafficking and synaptic plasticity that leads to dendritic spine regression, synaptic collapse, neuronal death and network failure in dementia.

We shall determine 1) how levels of protein SUMOylation are altered in human AD brain and animal models of dementia; 2) how SUMOylation regulates AMPAR trafficking in NMDAR-LTD and mGluR-LTD, and how this is affected in disease models of dementia 3) if manipulation of protein SUMOylation can be protective against synaptic dysfunction, synaptic loss and cognitive deficits in dementia.

We will use biochemical and histological analyses of post mortem human tissue in combination with functional and intervention studies in transgenic mouse models of dementia. The study will exploit a multidisciplinary array of techniques ranging from molecular biology, biochemistry and immunocytochemistry through electrophysiology and live cell imaging to animal behaviour. The applicants have complementary expertise and proven track records in all of these approaches.

Our ultimate aim is to identify one or more SUMO-substrate proteins that could provide tractable therapeutic targets to reduce or prevent synaptic dysfunction associated with dementia.

Who will benefit from this research and how will they benefit?

Dementia patients - Our ultimate goal is that the discoveries made from the work detailed in this proposal will eventually translate into solid therapeutically useful reagents that will treat, prevent and cure dementia. This could have major consequences in improving the quality of life.

Patients with other brain disorders - Identifying the roles and possible protective effects of SUMOylation in defective AMPAR trafficking will be relevant to many neurological and neurodegenerative disorders ranging from addiction through autism spectrum disorders to dementia and stroke.

Pharmaceutical industry - This project will reveal novel targets and pathways for therapeutic agents. Discoveries we make will have application beyond dementia to other clinically important brain diseases, which are huge clinical economic and social burdens in the UK and currently do not have effective treatments.

NHS - We hope that basic science discoveries and developments we make will feed into NHS research and the wider health system for translation, exploitation and application. Furthermore, effective preventative strategies could save many millions of pounds.

Academic colleagues and collaborators:- We enjoy an extensive and active network of collaborators in Bristol, the UK and in Europe. Tools, reagents and ideas generated in the course of this project will be are freely exchanged informally and, where appropriate, by more formal MTAs.

Information exchange with industry:- We have long-standing collaborations with GSK and a PhD student in Henley's lab will soon spend 6 months at GSK in Singapore. In addition, we have recent collaborations with UCB, Lundbeck on protein trafficking, Eli Lilly on synaptic function and networks. We intend to maintain and actively expand these collaborations, in part through former lab members now working in industry.

Potential commercial exploitation:- We do not foresee likely commercialization opportunities but we will consult with the University's Research and Enterprise Development office that have extensive experience and expertise.

Staff working on the project:- Bench scientists associated with the project will develop their molecular, biochemistry, imaging and electrophysiology skills. All researchers in our labs are encouraged to attend training courses to develop their general and specific skill sets, which significantly improve their career prospects. They will also be given the opportunity to develop skills in teaching and training undergraduate and postgraduate students.